The arrhythmogenic N53I variant subtly changes the structure and dynamics in the calmodulin N-terminal domain, altering its interaction with the cardiac ryanodine receptor.

ABSTRACT: Mutations in the genes encoding the highly conserved Ca²⁺-sensing protein calmodulin (CaM) cause severe cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia or long QT syndrome and sudden cardiac death. Most of the identified arrhythmogenic mutations reside in the C-terminal domain of CaM and mostly affect Ca²⁺-coordinating residues. One exception is the catecholaminergic polymorphic ventricular tachycardia-causing N53I substitution, which resides in the N-terminal domain (N-domain). It does not affect Ca²⁺ coordination and has only a minor impact on binding affinity toward Ca²⁺ and on other biophysical properties. Nevertheless, the N53I substitution dramatically affects CaM's ability to reduce the open probability

SUBMITTER: Holt C 

PROVIDER: S-EPMC7261784 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature